Synthesis of β‐Nicotinamide Riboside Using an Efficient Two‐Step Methodology

Abstract

A two-step chemical method for the synthesis of β-nicotinamide riboside (NR) is described. NR has achieved wide use as an NAD precursor (vitamin B3) and can significantly increase central metabolite NAD concentrations in mammalian cells. β-NR can be prepared with an efficient two-step procedure. The synthesis is initiated via coupling of commercially available 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose with ethyl nicotinate in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf). H NMR showed that the product was formed with complete stereoselectivity to produce only the β-isomer in high yield (>90% versus starting sugar). The clean stereochemical result suggests that the coupling proceeds via a cationic cis-1,2-acyloxonium-sugar intermediate, which controls addition by nucleophiles to generate predominantly β-stereochemistry. The subsequent deprotection of esters in methanolic ammonia generates the desired product in 85% overall yield versus sugar. © 2017 by John Wiley & Sons, Inc.

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

“…A new two-step one-pot procedure for the synthesis of β-NR + was reported by Sauve et al (Scheme 10) stemming from successively improved synthetic approaches [37–39]. The first step consisted in coupling of 1,2,3,5-tetra- O -acetyl-β-D-ribofuranose ( 2a ) with ethyl nicotinate ( 14 ) in the presence of 1 equivalent of TMSOTf in dry dichloromethane resulting in the stereoselective formation of the corresponding β-isomer 17 of O -ethyl nicotinate riboside in high yield.…”

“…These results indicated that methoxide is more reactive than ammonia in reacting with ester 17 . A very detailed synthetic procedure for the preparation of β-nicotinamide riboside triflate from ethyl nicotinate and 1,2,3,5-tetra- O -acetyl-D-β-ribofuranose is provided in this article [39]. The purification of the final NR + OTf − was achieved by reversed phase column chromatography on a C18 column (activated with MeOH/water systems) using water as an eluent.…”

“…These observations highlight the need for special appreciations for the chemical stability of the glycosidic bond in NR + when conducting chemical reactions and choosing appropriate work-up procedures for NR + /NRH derivatives, as this class of nucleoside greatly differs from the canonical purine and pyrimidine nucleosides. For instance, the glycosyl bond of NR + was shown to be very susceptible to cleavage in methanolic solutions of ammonia [39]. As such, to get the corresponding deprotected NR + salt in good yields and free of admixtures, removal of acetate groups from 3-(carbamoyl)-1-(2,3,5-tri- O -acetyl-β-D-ribofuranosyl)pyridinium salt (NR + triacetate) should be conducted under specifically controlled conditions (e.g., using ammonia in anhydrous methanol at −3 to −5 °C as recommended by Lee et al [27]), and with subsequent – after the completion of deacetylation – evaporating excessive ammonia at temperatures also below 0 °C [25,39].…”

“…For instance, the glycosyl bond of NR + was shown to be very susceptible to cleavage in methanolic solutions of ammonia [39]. As such, to get the corresponding deprotected NR + salt in good yields and free of admixtures, removal of acetate groups from 3-(carbamoyl)-1-(2,3,5-tri- O -acetyl-β-D-ribofuranosyl)pyridinium salt (NR + triacetate) should be conducted under specifically controlled conditions (e.g., using ammonia in anhydrous methanol at −3 to −5 °C as recommended by Lee et al [27]), and with subsequent – after the completion of deacetylation – evaporating excessive ammonia at temperatures also below 0 °C [25,39]. Moreover, because of the limitations associated with different stability to different pH ranges, the reduction of NR + to NRH must be performed in slightly basic media, such as saturated sodium bicarbonate solution [19,31].…”

The chemistry of the vitamin B3 metabolome

“…While several routes and optimization studies have been conducted [126] since the first synthetic route development, the most versatile uses tetra-acylated ribosides and TMSOTf as a catalyst [127,128]. Sauve and coworkers improved on the method and reported a very efficient one-pot procedure for the synthesis of β-NR from ethyl nicotinate [129,130]. Both routes generate the triflate salt forms of NR.…”